Certain types of human papillomaviruses (HPVs) are frequently detected in human genital cancers, and therefore are designated high risk types, while other types are frequently detected in benign genital lesions, but rarely in carcinomas, and so have been designated low risk types. We have undertaken a comparative analysis of the gene products of high risk and low risk viruses in an attempt to gain insight into the important determinants of pathogenicity for the genital HPVs. The expression and activities of the E6 and E7 genes have been investigated because they are selectively retained and expressed in genital cancers. We have determined that the E6s and E7s of the two viral classes differ in their ability to induce cellular transformation and immortalization, with the apparent oncogenic potential of the viruses correlating with the in vitro activities of both E6 and E7. E6 and E7 also activate transcription of test promoters but there does not appear to be a correlation between trans-activation and oncogenic potential. We have also determined that the E7s of high and low risk types differ in their ability to be expressed from polycistronic mRNAs. The mechanisms of E6 and E7 induced transformation and immortalization are under investigation. For E6, we have determined the full-length protein product, but not the truncated E6* proteins unique to the high risk types, is required for these activities. Additional studies indicated that mutant p53 can functionally substitute for E6 (but not E7) in the immortalization of normal human keratinocytes but not in the transformation assay, suggesting that an interaction with wild type p53 may be important for immortalization but that a separable E6 function may be required for transformation. For E7, we are currently identifying the cellular proteins with which E7 interacts and evaluating the biological significance of these interactions. In studies of Bovine papillomavirus (BPV) induced transformation of rodent fibroblasts, we have found that E5, the major transforming gene of BPV, can cooperate with a co-transfected ras gene in the induction of transformation.